Protein tyrosine phosphatases in glioma biology

Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic strategies. The drastically increased knowledge about the molecular underpinnings of gliomas during the last decade has elicited high expectations for a more rational and effective therapy for these tumors. Most studies on the molecular pathways involved in glioma biology thus far had a strong focus on growth factor receptor protein tyrosine kinase (PTK) and phosphatidylinositol phosphatase signaling pathways. Except for the tumor suppressor PTEN, much less attention has been paid to the PTK counterparts, the protein tyrosine phosphatase (PTP) superfamily, in gliomas. PTPs are instrumental in the reversible phosphorylation of tyrosine residues and have emerged as important regulators of signaling pathways that are linked to various developmental and disease-related processes. Here, we provide an overview of the current knowledge on PTP involvement in gliomagenesis. So far, the data point to the potential implication of receptor-type (RPTPδ, DEP1, RPTPμ, RPTPζ) and intracellular (PTP1B, TCPTP, SHP2, PTPN13) classical PTPs, dual-specific PTPs (MKP-1, VHP, PRL-3, KAP, PTEN) and the CDC25B and CDC25C PTPs in glioma biology. Like PTKs, these PTPs may represent promising targets for the development of novel diagnostic and therapeutic strategies in the treatment of high-grade gliomas

Experiences with Family Planning amongst Persons with Mental Health Problems: A Nationwide Patient Survey

High rates of unintended pregnancies in patients with mental health problems reflect the unmet need for tailored family planning. This study aims to explore aspects of family planning that are especially challenging for patients experiencing health problems by obtaining the perspective of (former) patients and those with close relationships with the (former) patients. In August 2021, members of a Dutch national mental health panel, consisting of (former) patients and close ones, were invited to respond to a 34-question online survey that included questions on four domains: reproductive history, decision making, parenting, and sexuality. This study has revealed the severe and adverse impact of mental health problems across all of the four domains of reproductive health and family planning, which the questions specifically targeted. Based on these results, we recommend discussing family planning with all patients experiencing or at risk for mental health problems and their partners. These discussions should address a desire to have children, (involuntary) childlessness, uncertainties about parenting and sexuality, while remaining considerate of experienced taboos

Experiences with Family Planning amongst Persons with Mental Health Problems: A Nationwide Patient Survey

High rates of unintended pregnancies in patients with mental health problems reflect the unmet need for tailored family planning. This study aims to explore aspects of family planning that are especially challenging for patients experiencing health problems by obtaining the perspective of (former) patients and those with close relationships with the (former) patients. In August 2021, members of a Dutch national mental health panel, consisting of (former) patients and close ones, were invited to respond to a 34-question online survey that included questions on four domains: reproductive history, decision making, parenting, and sexuality. This study has revealed the severe and adverse impact of mental health problems across all of the four domains of reproductive health and family planning, which the questions specifically targeted. Based on these results, we recommend discussing family planning with all patients experiencing or at risk for mental health problems and their partners. These discussions should address a desire to have children, (involuntary) childlessness, uncertainties about parenting and sexuality, while remaining considerate of experienced taboos

Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells: <it>FLT3 ITD sustains high levels of DUSP6 expression</it>

Abstract Protein-tyrosine phosphatases (PTPs) are important regulators of cellular signaling and changes in PTP activity can contribute to cell transformation. Little is known about the role of PTPs in Acute Myeloid Leukemia (AML). The aim of this study was therefore to establish a PTP expression profile in AML cells and to explore the possible role of FLT3 ITD (Fms-like tyrosine kinase 3 with internal tandem duplication), an important oncoprotein in AML for PTP gene expression. PTP mRNA expression was analyzed in AML cells from patients and in cell lines using a RT-qPCR platform for detection of transcripts of 92 PTP genes. PTP mRNA expression was also analyzed based on a public microarray data set for AML patients. Highly expressed PTPs in AML belong to all PTP subfamilies. Very abundantly expressed PTP genes include PTPRC, PTPN2, PTPN6, PTPN22, DUSP1, DUSP6, DUSP10, PTP4A1, PTP4A2, PTEN, and ACP1. PTP expression was further correlated with the presence of FLT3 ITD, focusing on a set of highly expressed dual-specificity phosphatases (DUSPs). Elevated expression of DUSP6 in patients harboring FLT3 ITD was detected in this analysis. The mechanism and functional role of FLT3 ITD-mediated upregulation of DUSP6 was then explored using pharmacological inhibitors of FLT3 ITD signal transduction and si/shRNA technology in human and murine cell lines. High DUSP6 expression was causally associated with the presence of FLT3 ITD and dependent on FLT3 ITD kinase activity and ERK signaling. DUSP6 depletion moderately increased ERK1/2 activity but attenuated FLT3 ITD-dependent cell proliferation of 32D cells. In conclusion, DUSP6 may play a contributing role to FLT3 ITD-mediated cell transformation.</p

Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells : FLT3 ITD sustains high levels of DUSP6 expression

Protein-tyrosine phosphatases (PTPs) are important regulators of cellular signaling and changes in PTP activity can contribute to cell transformation. Little is known about the role of PTPs in Acute Myeloid Leukemia (AML). The aim of this study was therefore to establish a PTP expression profile in AML cells and to explore the possible role of FLT3 ITD (Fms-like tyrosine kinase 3 with internal tandem duplication), an important oncoprotein in AML for PTP gene expression. PTP mRNA expression was analyzed in AML cells from patients and in cell lines using a RT-qPCR platform for detection of transcripts of 92 PTP genes. PTP mRNA expression was also analyzed based on a public microarray data set for AML patients. Highly expressed PTPs in AML belong to all PTP subfamilies. Very abundantly expressed PTP genes include PTPRC, PTPN2, PTPN6, PTPN22, DUSP1, DUSP6, DUSP10, PTP4A1, PTP4A2, PTEN, and ACP1. PTP expression was further correlated with the presence of FLT3 ITD, focusing on a set of highly expressed dual-specificity phosphatases (DUSPs). Elevated expression of DUSP6 in patients harboring FLT3 ITD was detected in this analysis. The mechanism and functional role of FLT3 ITD-mediated upregulation of DUSP6 was then explored using pharmacological inhibitors of FLT3 ITD signal transduction and si/shRNA technology in human and murine cell lines. High DUSP6 expression was causally associated with the presence of FLT3 ITD and dependent on FLT3 ITD kinase activity and ERK signaling. DUSP6 depletion moderately increased ERK1/2 activity but attenuated FLT3 ITD-dependent cell proliferation of 32D cells. In conclusion, DUSP6 may play a contributing role to FLT3 ITD-mediated cell transformation

Identification of VHY/Dusp15 as a Regulator of Oligodendrocyte Differentiation through a Systematic Genomics Approach

<div><p>Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease. We have undertaken a systematic genomic approach to evaluate PTP gene activity in multiple sclerosis autopsies and in related <em>in vivo</em> and <em>in vitro</em> models of the disease. This effort led to the identification of Dusp15/VHY, a PTP previously believed to be expressed only in testis, as being transcriptionally regulated during OL differentiation and in MS lesions. Subsequent RNA interference studies revealed that Dusp15/VHY is a key regulator of OL differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation.</p> </div

Additional file 4: of Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma

Immunohistochemical staining for PTPRT on formalin-fixed paraffin-embedded materials. (PDF 303 kb

Ten-point standardized rating scale for EAE clinical score monitoring.

<p>The final score for each animal is determined by the addition of all the above mentioned categories. Note: Score  =  15 for dead animal.</p

Phosphatase activity of GST-tagged full length Dusp15/VHY.

<p>A. Dusp15 phosphatase activity was assessed using the DiFMUP (6,8-difluoro-4-methyumbelliferyl phosphate) assay at the experimentally optimal enzyme concentration of 4 ng/mL. B. Optimal pH activity (pH 6) was determined by testing a pH range from pH 3 to 8. C. and D. Activity of Dusp15/VHY on phospho-peptides substrates corresponding respectively to pY₁₁₉ and pY₇₇₁ dephosphorylation sites of SNX6 (NED(pY₁₁₉)AGYIIPPAP) and PDGFR-β (IESSN(pY₇₇₁)MAPYD). VHY/Dusp15 was used at 4 ng/mL at pH6 and activity was detected using the Malachite Green phosphate detection assay. OD, Optical Density at 620 nm. Dissociation constant (Km) was calculated as the substrate concentration needed to reach V_max/2 and expressed as Mean ± S_EM of three different experiments.</p